Throughout this application various publications are referred to by arabic numerals within parenthesis. Full bibliographic citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures for the publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
It has long been known that dietary restriction of vitamin A causes widespread abnormalities in tissue and organ physiology, especially in neonates. The vitamin A deficiency syndrome is characterized by generally stunted growth, keratoses of skin and eyes (1) (leading in severe cases to blindness), defective testis development (2) etc., and atrophy of central (i.e., thymus and bursa of Fabrizius) and peripheral lymphoid organs. Consequently, immune functions are severely affected. Even in mild cases of vitamin A deficiency, the immune system appears to be hyporesponsive. In a recent study in southern India (4), the authors noted that children suffering from mild vitamin A deprivation had significantly higher mortality rates from common childhood diseases compared with children receiving normal dietary levels of vitamin A. Since severity of infection but not susceptibility to infection was correlated with vitamin A deprivation, it is likely that reduced immune functions are a factor.
In the absence of retinol, lymphoblastoid cells (LCL) die within 24 to 48 hours. (5) Retinol and retinaldehyde, but not retinoic acid, support the growth of LCL in serum-free medium. The same is true for activated human thymocytes. These findings may represent direct correlations to the lagging development of lymphoid organs described by Wolbach and Howe (3) and the in-vivo immune system dysfunction referred to earlier. (4)
Nearly all vertebrate tissues are bathed in a constant supply of vitamin A, and the ubiquitous distribution of cellular retinol-binding protein (CRBP) with its high affinity to retinol suggests that retinol is inside most cells as well. Yet the general purpose of retinol, its metabolism and final destination, remain for the most part unknown, the well-studied example of specialized usage in vision notwithstanding. Since retinol is not known to be incorporated into structural parts of cells and does not bind to one of the yet analyzed transcription factors with high enough affinity, its role is more likely to be found in its function as a precursor for derivatives. Use of retinaldehyde in vision is one example, and another that of retinoic acid as a morphogen (6), important for development of the limb and brain. When coupled with parallel discoveries of retinoic acid receptors (RAR) (7A-7C) within the larger steroid receptor superfamily (8), a sound molecular foundation is given. In this hypothesis, RARs bind to specific response elements in the promoter regions of genes. Retinoic acid in turn binds to RAR, causing activation of gene transcription. The universal principle of this genetic control has increasingly been highlighted by observations that many developmentally important genes from drosophila to man are part of the retinoic acid/steroid receptor superfamily. Moreover, for more than two dozen "orphan receptors" (9) engaged in control of the general physiology of cells, the ligands are not known and are suspected to be small lipophilic molecules.
In analogy to retinoic acid, other members of the retinoid family may also serve as transcriptional activators. This concept has been pursued in the current invention leading to the discovery of a retinoid molecule hitherto unknown in nature, that can activate certain physiological processes in .beta. lymphocytes. This new compound, 14 hydroxy-4,14-retro-retinol(14-hydroxy-reto .alpha. retinol), may work along a pathway parallel to the well established retinoic acid pathway, but leading to distinct physiological responses.